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Systems genetics analysis of tumor evolution in the mouse

小鼠肿瘤进化的系统遗传学分析

基本信息

批准号：
10621723
负责人：
ALLAN BALMAIN
金额：
$ 93.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10621723
关键词：
Animals Benign Biological Markers Biological Models Cancer Model Cancer-Predisposing Gene Cause of Death Cells Chemicals Complex Databases Distant Metastasis Environment Environmental Exposure Evolution Exposure to Frequencies Funding Genes Genetic Genetic Determinism Genomics Genotype Goals Head and neck structure Human Immune checkpoint inhibitor Immunotherapy Inherited Lesion Lung Malignant - descriptor Malignant Neoplasms Modeling Mouse Strains Mus Mutagens Mutation Neoplasm Metastasis Outcome Pathway Analysis Pathway interactions Population Primary Carcinoma Proteins Radiation Research Risk Route Sampling Series Signal Pathway Skin Carcinogenesis Skin Carcinoma Squamous cell carcinoma System Technology Testing Tissue Banks Tumor Bank Tumor Promotion carcinogenesis carcinogenicity cohort genetic analysis genome-wide genomic profiles human model individual patient mouse model mutant neoantigens novel novel therapeutics response tool translational study tumor tumor DNA

项目摘要

Abstract Systems Genetics Analysis of Tumor Evolution in the Mouse. Metastasis is the major cause of death due to cancer in humans, but many factors play a role in determining the route taken by initiated cells to reach this end stage. We know that tumors arise due to the combined effects of inherited genetic factors and environmental exposures, and have taken the long term view that successful modeling of human cancer in the mouse requires us to take account of interactions between genetics and environment. The over-arching goal of this research is to develop an integrated systems genetics view of the cells, signaling pathways and mutations in specific genes involved in evolution of metastasis from single initiated cells, using one of the best characterized models of multistage carcinogenesis of the skin. Based on major funding from the NCI MMHCC over the past 15 years, we have built up a unique tissue and tumor bank comprising thousands of samples of Ras-mutant squamous tumors from a genetically heterogeneous mouse population. These samples encompass all stages from benign lesions to metastases, and in particular include hundreds of matched primary carcinomas and distant metastases from the same animals. All tumors were induced by exposure to mutagens and tumor promoting agents, resulting in complex genomic landscapes that resemble, in mutation frequency and type, the genomic profiles of human squamous carcinomas of the skin, head and neck, and lung. All mice in the cohort have been genotyped genome-wide to facilitate linkage and eQTL analysis to identify genetic determinants of initiation, benign tumor formation, progression and metastatic dissemination. This project will exploit this unique tissue bank and database by using genomic technologies, together with novel mouse strains, to identify the cells of origin of benign and malignant tumors, biomarkers of risk of malignant progression, and genetic drivers of metastasis. Computational network analysis tools will be used to study the evolution of signaling pathways, for example the Ras pathway, through multiple stages of carcinogenesis, to identify changes in these networks that will identify potential novel cancer target genes. Finally we will initiate a new series of translational studies of immunotherapy, based on our observation that these chemically induced tumors harbor novel neo-antigens and show promising responses to inhibitors of immune checkpoint proteins.

摘要

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The mutational signature profile of known and suspected human carcinogens in mice.

DOI：
10.1038/s41588-020-0692-4
发表时间：
2020-11
期刊：
Nature genetics
影响因子：
30.8
作者：
Riva L;Pandiri AR;Li YR;Droop A;Hewinson J;Quail MA;Iyer V;Shepherd R;Herbert RA;Campbell PJ;Sills RC;Alexandrov LB;Balmain A;Adams DJ
通讯作者：
Adams DJ

The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk.